Evolution of Therapeutic Modalities: FDA Approvals and Innovation Landscape

Comparison of FDA drug approvals by modality over 50 years vs. the past 20 years, illustrating the shift from small-molecule dominance to increased biologics and advanced therapies.

Small molecules – low molecular weight compounds typically made by chemical synthesis – have been the bedrock of pharmacotherapy for most of modern history. They include the vast majority of conventional pills and injectables for diseases ranging from infections to chronic illnesses. Over the past 50 years, small-molecule drugs constituted the overwhelming majority of FDA approvals – on the order of ~80–85% of new therapeutics [2][3]. Even in recent decades, small molecules continued to dominate: for example, in 2021, 72% of FDA novel drug approvals were small molecules (36 of 50 NMEs), versus 28% biologics [1]. This roughly 3:1 ratio of small molecules to large molecules has been consistent in the late 2010s and early 2020s [1]. Over the past 20 years (2005–2024), we still see about ~70% of new approvals as small molecules, though this is a decrease in share compared to earlier decades. Small molecules thus remain a mainstay of therapy, thanks to well-established development pathways and often simpler manufacturing and administration (typically oral pills) compared to biologics.

However, the dominance of small molecules has gradually eroded as new modalities emerged. In 2019, small molecules comprised ~79% of new approvals, but by 2024 their share had declined to ~62% [3]. Industry trends also show R&D investment shifting: in 2014, ~55–60% of pharma R&D spend was on small molecules, dropping to ~40–45% by 2024 as biologics gained focus [3]. Nonetheless, innovation in small molecules continues (with novel mechanisms like protein degraders, allosteric inhibitors, etc.), and hundreds of small-molecule candidates remain in late-phase pipelines for diseases such as cancer, cardiovascular and metabolic disorders, and infectious diseases. The resilience of small molecules is evident – even in 2024 they accounted for the majority of approvals and showed “staying power” despite the biologics boom [4]. We can expect small molecules to continue contributing a large share of new drugs, even as their relative proportion falls in favor of newer modalities.

Monoclonal antibodies are large protein drugs designed to bind specific antigens – a modality that launched the biologic drug revolution. The first therapeutic mAb was approved in 1986 (muromonab-CD3 for transplant rejection), and since then over 100 therapeutic mAbs have been approved by the FDA [5]. In fact, by 2021 the FDA had approved its 100th monoclonal antibody product, roughly 35 years after the first; today mAbs make up a substantial portion of new drugs [5]. Monoclonal antibodies now account for “nearly a fifth of the agency’s new drug approvals each year” [5]. For example, in 2023 the FDA approved 12 mAbs (out of 55 new drugs), the highest annual number to date [6]. Overall, mAbs represent about 20% of recent approvals and have become a cornerstone of treatments in oncology, immunology, and other fields [5].

Regulatory landscape: Monoclonal antibodies are regulated as biologics (via Biologics License Applications). The FDA’s Center for Drug Evaluation and Research (CDER) began overseeing many biologic mAb approvals after 2003, which simplified tracking approvals in this category [3]. Many blockbuster biologics (e.g. anti-TNF mAbs for autoimmune diseases, checkpoint inhibitor mAbs for cancer) have reached the market, establishing regulatory precedents. The FDA has also approved biosimilar mAbs in recent years, increasing competition.

Innovation landscape: A large number of mAbs are in late-stage development for diverse conditions. These include next-generation antibody formats like bispecific antibodies (which can bind two targets) – the FDA approved its first bispecifics in 2022–2023 for oncology, and more are in Phase 3 trials. In 2023, two bispecific antibodies were approved, continuing a trend of recent years [6]. Engineers are also improving mAbs’ properties (e.g. fragment antibodies, antibody fragments for tissue penetration, antibody-drug conjugates described below). With mAbs comprising ~50% of biologics approved in recent years [7], it’s clear this modality will remain a major focus. Dozens of mAbs targeting novel pathways (for Alzheimer’s, severe asthma, rare diseases, etc.) are in Phase 3, and many more are advancing, ensuring a strong pipeline of antibody therapies.

Antibody-drug conjugates combine the targeting specificity of monoclonal antibodies with the cell-killing power of cytotoxic small molecules. An ADC is essentially a monoclonal antibody linked to a potent drug payload, allowing targeted delivery of chemotherapy or toxins directly to cells bearing a specific antigen (often cancer cells) [8]. This modality offers a way to increase efficacy and limit systemic toxicity in cancer therapy. The concept was proven with the first FDA-approved ADC, gemtuzumab ozogamicin (Mylotarg) in 2000 for leukemia, though that product was initially withdrawn and later re-introduced. Since then, ADC technology has matured significantly.

Regulatory landscape: As of late 2023, the FDA has approved 15 different ADCs for cancer treatment [8]. Notably, the pace of ADC approvals has accelerated in the past few years. For example, 2020–2022 saw multiple ADC approvals (e.g. trastuzumab deruxtecan, sacituzumab govitecan, enfortumab vedotin, mirvetuximab soravtansine, etc.), targeting breast cancer, urothelial cancer, ovarian cancer and more. ADCs are regulated as biologics (due to the antibody component), but they require extensive CMC (chemistry, manufacturing, controls) evaluation for the conjugation chemistry and payload stability. FDA has released guidances specific to ADC development given their complexity.

Innovation landscape: ADCs are a booming area of oncology R&D, often described as “guided missiles” against cancer. Over 100 ADCs are in clinical development across various stages [8]. Many large pharmaceutical companies have invested heavily in ADC platforms and partnerships. Late-stage pipelines include ADCs for novel targets (beyond HER2 or TROP-2) and improved linkers/payloads (e.g. using DNA-damaging pyrrolobenzodiazepine (PBD) toxins or new auristatins). While no ADC was approved in 2023, several were on the cusp – indicating more approvals likely in 2024–2025 [6]. The innovation includes next-gen ADCs that can carry dual payloads or use cleavable linkers activated in the tumor microenvironment. Given the strong clinical trial results for many ADCs (with some achieving breakthrough therapy designations), we expect the FDA to approve a steady stream of new ADCs in coming years, further increasing their proportion among drug approvals.

RNA-based therapies, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), represent a modality that directly targets RNA to modulate gene expression. These approaches can block protein translation, degrade messenger RNA, or modify splicing patterns, allowing treatment of diseases at their genetic root [9].

Regulatory landscape: The first antisense drug (fomivirsen) was approved in 1998, followed by landmark approvals like nusinersen for spinal muscular atrophy and patisiran for hereditary amyloidosis. As of 2023, around a dozen RNA-targeting drugs (ASO and siRNA) have FDA approval, with four approvals in 2023 alone [9]. The FDA continues to refine guidelines for manufacturing and safety assessments of these molecules, including off-target evaluation and delivery technologies like GalNAc conjugates.

Innovation landscape: The pipeline for RNA therapeutics is expanding rapidly, with dozens of late-stage candidates targeting rare genetic diseases, cardiovascular conditions, and neurodegenerative disorders. siRNA therapies such as inclisiran for hypercholesterolemia and vutrisiran for amyloidosis exemplify the modality’s maturing clinical impact. Meanwhile, mRNA vaccines, validated by COVID-19, are paving the way for therapeutic mRNA approaches beyond infectious disease [9].

mRNA-based therapies use messenger RNA to transiently express proteins in the patient’s cells, offering a way to direct the body’s own cells to produce a therapeutic protein or antigen. This modality was dramatically validated by the success of mRNA vaccines for COVID-19, with the FDA approving Comirnaty (Pfizer-BioNTech) and Spikevax (Moderna) in 2021 [10]. These approvals demonstrated that mRNA delivered in lipid nanoparticles can be safe and highly effective on a global scale.

Regulatory landscape: As of 2025, only two mRNA-based products are FDA-approved (both vaccines). Regulatory agencies rapidly adapted to evaluate mRNA platforms during the pandemic and have established guidance for manufacturing (e.g., purity, sequence fidelity, and lipid nanoparticle characterization). This framework now supports evaluation of both vaccine and therapeutic mRNA candidates, including emerging non-vaccine uses.

Innovation landscape: The pipeline for mRNA therapeutics is highly active, with multiple late-stage vaccine candidates for RSV and influenza and therapeutic programs for cancer (personalized neoantigen vaccines) and rare diseases. While mRNA therapies currently represent a tiny fraction of total drug approvals, their scalability and adaptability position them as a major growth area in the coming decade [10].

Gene therapy entails delivering genetic material (DNA or RNA) into a patient’s cells to treat or cure disease – often by replacing a defective gene or providing a new gene function. After decades of research and some setbacks, gene therapy has entered an era of tangible clinical success. The FDA approved its first in vivo gene therapy in 2017 (Luxturna, an AAV vector delivering RPE65 gene for inherited retinal dystrophy), followed by a growing number of approvals for other diseases. In a broader definition including ex vivo genetically modified cells, the first FDA gene therapy product was approved in 2017 as well (Kymriah, a CAR-T cell therapy for leukemia, which is genetically engineered T cells) [bioinformant.com]. As of early 2025, the FDA’s Office of Therapeutic Products (previously OTAT) has approved 43 cell and gene therapy products [bioinformant.com]. This includes various types: around 15 gene therapies (delivering genes via viral vectors), 7 CAR-T cell therapies, as well as other cell-based therapies [bioinformant.com]. These approvals span rare genetic diseases and oncology.

Regulatory landscape: Gene therapies are regulated as biologics and often require extensive review by FDA advisory committees due to their complexity and potential risks. They often receive orphan drug status and breakthrough designations given their focus on serious rare diseases [mdpi.com]. Key FDA approvals in this category include AAV vector therapies like Luxturna (eye disease), Zolgensma (spinal muscular atrophy, approved 2019), lentiviral vector therapies like betibeglogene (Zynteglo for beta thalassemia, 2022) and elivaldogene (Skysona for CALD, 2022), and others for hemophilia (Roctavian and Hemgenix, approved 2022–2023). Each approval has been a landmark: for example, Roctavian in 2023 became the first gene therapy for hemophilia A [childrenshospital.org]. The FDA has issued specific guidance on human gene therapy products, and in 2024 reorganized the CBER office to specifically oversee cell and gene therapies, reflecting the growing pipeline. A major regulatory consideration is long-term safety (integration risks, immunogenicity), so approvals often come with requirements for long-term patient follow-up (15 years for some products).

Innovation landscape: The gene therapy pipeline is robust, targeting dozens of monogenic diseases as well as some chronic conditions. There are many late-stage programs: for instance, gene therapies for sickle cell disease were in Phase 3 and approved at end of 2023 (more on that under gene editing) [childrenshospital.org], and others for muscular dystrophy (Sarepta’s SRP-9001 for Duchenne, which was approved in 2023 as Elevidys [childrenshospital.org]). Additional AAV therapies for hemophilia B and A were approved (Hemgenix, Roctavian) and others for Huntington’s or ALS are in trials. Ex vivo gene therapies (where patients’ cells are modified outside the body) also continue to expand – beyond CAR-T, there are gene-modified stem cell transplants (like Bluebird Bio’s therapies for beta-thalassemia and CALD). Overall dozens of gene therapy candidates are in Phase 3, and many more in earlier phases for conditions ranging from metabolic disorders to vision loss. The innovation focus now includes improving vectors (e.g. novel AAV serotypes for broader tissue targeting), non-viral gene delivery (like lipid nanoparticles for gene therapy), and strategies to control transgene expression. As these reach fruition, we anticipate rapid growth in gene therapy approvals. Indeed, 2023 was called a “landmark year for cell and gene therapy approvals”, with multiple first-in-class gene therapies reaching the market [cgtlive.com].

Cell therapy involves administering live cells to patients as treatments. Some cell therapies are engineered (gene-modified) – for example, CAR-T cells where a patient’s T lymphocytes are modified to express a chimeric antigen receptor to attack cancer – and others are unmodified or donor-derived cells (such as stem cell transplants or tissue-engineered cells). The line between cell and gene therapy often overlaps (CAR-T are gene-edited cells, so they fall in both categories) [bioinformant.com]. Nonetheless, cell therapies as a class have become established in certain areas. The FDA has approved several CAR-T cell therapies: the first were Kymriah and Yescarta in 2017 for refractory leukemias/lymphomas, and now a total of 7 CAR-T products are approved (for various blood cancers) [bioinformant.com]. Additionally, the FDA has approved cell therapy products like hematopoietic stem cell-rich cord blood for transplantation (multiple cord blood bank products were licensed) [bioinformant.com], as well as bespoke cell therapies for specific conditions (e.g. Rethymic, a cultured thymus tissue product for pediatric immune disorder, approved in 2021).

Regulatory landscape: Cell therapies are regulated by the FDA’s OTAT as biologics. They pose challenges in consistency (living cells are variable) and logistics (some are patient-specific autologous therapies). The FDA has put in place risk evaluation and mitigation strategies (REMS) for CAR-T therapies due to risks like cytokine release syndrome. By early 2025, the FDA had to oversee the surge in cell/gene therapy applications – in fact the number of cell/gene therapy INDs and BLAs has grown so much that FDA projected 10–20 cell/gene therapy approvals per year by 2025 (a projection from prior statements). The current count of approved cell/gene therapies (43 total as noted) includes 12 cell therapies that are not cord blood (this category could include things like allogeneic stem cell products, tissue-engineered products, etc.) [bioinformant.com]. The agency continues to refine guidance on manufacturing (CMC) for cell therapies, such as potency assays for living cells.

Innovation landscape: The cell therapy pipeline is vibrant, especially in oncology. Beyond the approved CAR-Ts for B-cell malignancies, multiple next-gen CAR-T and TCR-T cell therapies are in late trials (targeting solid tumor antigens, using gene edits to enhance persistence, etc.). Companies are also exploring allogeneic “off-the-shelf” cell therapies (e.g. using donor T cells or NK cells, gene-edited to avoid rejection) – some of which are in Phase 2/3. Outside of cancer, cell therapies like mesenchymal stem cells (MSCs) are being tested for regenerative medicine (e.g. for heart failure or Crohn’s disease fistulas), though results have been mixed and only a few (like an MSC product Ryoncil for pediatric graft-versus-host disease) have reached approval [bioinformant.com]. We also see novel cell types: retinal cell transplants for macular degeneration (in trials), islet cell transplants for diabetes, and others. While not all these will succeed, the late-stage pipeline includes enough promising cell therapies that we expect the number of approved products to continue climbing steadily. Cell therapies are still a small share of total drug approvals by count (just a few dozen out of thousands), but their clinical impact (e.g. curing ~40–50% of refractory leukemia patients with CAR-T) is transformative in their niches.

Radiopharmaceuticals are drugs that deliver radioactive isotopes to specific tissues, enabling targeted radiation therapy (or imaging). Therapeutically, these often consist of a radionuclide attached to a targeting molecule (which could be a small molecule or antibody) that carries it to tumors where the radiation can destroy cells. This modality has existed for decades – a classic example is radioactive iodine (I-131) treatment for thyroid disorders, used since the 1940s. In the past 20 years, there has been a renaissance in targeted radiopharmaceutical therapy for cancer. The FDA has approved a handful of modern radiotherapeutics, including iodine-131 tositumomab (Bexxar, 2003) and yttrium-90 ibritumomab tiuxetan (Zevalin, 2002) for lymphoma (radio-immunotherapies), radium-223 dichloride (Xofigo, 2013) for metastatic prostate cancer (targets bone), lutetium-177 dotatate (Lutathera, 2018) for neuroendocrine tumors, and lutetium-177 PSMA-617 (Pluvicto, 2022) for metastatic prostate cancer.

Regulatory landscape: Radiopharmaceuticals are approved by the FDA as drugs, but their use also involves oversight by nuclear regulatory bodies due to radioactivity. The FDA assesses the safety/efficacy like any drug (looking at tumor response, survival, etc.), with added considerations for radiation safety. To date, the number of approved therapeutic radiopharmaceuticals remains small (only a few), reflecting that this is a niche modality. For example, “the latest FDA-approved radiopharmaceuticals available to patients include Lutathera, Pluvicto, and Xofigo” among a short list [karmanos.org]. These agents have very specific indications and require specialized administration (often in nuclear medicine facilities).

Innovation landscape: Interest in radiopharmaceuticals is rapidly expanding. Several large companies (Novartis, Bayer, Merck) have invested in this space, seeing it as an important frontier in oncology. The pipeline includes new radioisotopes (e.g. alpha-emitters like Actinium-225 or Lead-212 that deliver higher-energy, shorter-range radiation) and new targeting molecules (small molecule ligands for receptors on tumors, antibody fragments, etc.). One example in late-stage development is an Actinium-225 labeled PSMA ligand for prostate cancer, which is in Phase 3. Another is a theranostic pairing of a new neurotensin receptor antagonist radioligand for pancreatic cancer. While these are still experimental, early trial data are encouraging. We anticipate more Phase 3 trials completing in the next 1–2 years for radiopharmaceuticals, which could lead to FDA approvals. If successful, radiopharmaceuticals could move from a ultra-niche to a more mainstream adjunct therapy in oncology. Still, in terms of numbers, radiotherapy drugs will likely remain a small slice of overall approvals (on the order of <1% historically, with just a handful of products) – but a very important slice for certain patient populations.

In summary, the therapeutic modalities available today are far more diverse than 50 years ago. Small molecules dominated drug development through the late 20th century, comprising roughly 80–90% of all approvals [nature.com]. Biologic modalities were virtually nonexistent in the 1970s, but they have expanded to claim a significant share: in the past 20 years, about 25–30% of new drug approvals have been biologics (proteins, peptides, antibodies) [dcatvci.org]. Within biologics, monoclonal antibodies stand out as a mature and major class (~20% of recent approvals) [nature.com]. Newer modalities like oligonucleotides, gene therapies, cell therapies, and radiopharmaceuticals have emerged from fringe concepts to real approved treatments in the last two decades – albeit each still represents only a few percent (or less) of total approvals by count. For example, the FDA has now approved dozens of cell and gene therapies (43 as of 2025) [bioinformant.com], and around 15 oligonucleotide drugs (with four approved in 2023 alone) [oligofastx.com]. The modalities pie charts above vividly illustrate this shift: small molecules still form the bulk, but the slice taken by advanced modalities has grown markedly from the 1975–2000 era to the 2005–2025 era.

Looking ahead, both the regulatory landscape and innovation landscape point to a continued broadening of modality options. The FDA has been adapting its frameworks (creating specialized review teams, issuing new guidances) to accommodate cell/gene therapies, genomic medicines, and other novel approaches. Meanwhile, the late-stage pipeline suggests that in the next 5–10 years we will see: more gene therapies for common diseases (not just ultra-rare disorders), the first wave of in vivo CRISPR gene editing therapies, routine use of mRNA vaccines beyond COVID-19, and possibly entirely new categories (e.g. gene silencing epigenetic edits, microbiome therapies, etc.). Biologics as a whole are expected to rival or surpass small molecules in share of new approvals by the late 2020s if current trends continue [chemaxon.com][chemaxon.com].

In conclusion, drug development has transformed into a modality-agnostic pursuit of therapeutic effect: whether via a pill, a protein, or a gene-altering injection, the goal is to treat disease in fundamentally new ways. Patients are already benefiting from treatments once considered science fiction – such as silencing a gene with a small RNA or reprogramming immune cells to hunt cancer. As the innovation engine continues and regulatory support remains strong, we can expect the therapeutic arsenal to become even more modality-diverse, fulfilling medical needs that were untreatable just a decade or two ago. The pie chart of approvals in 2045 may look unrecognizable compared to 50 years ago – and that is good news for medicine and humanity.